This proposal seeks continued funding for the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium, a multicenter, multidisciplinary team which has the goal to identify susceptibility genes for :amilial pancreatic cancer (FPC). The PACGENE Consortium has shown that coordinated case finding, :amily recruitment, and linkage analysis are productive: we have identified novel putative regions on at least 4 chromosomes, and are positioned to use the pedigree material to further gene discovery. The PACGENE onsortium comprises 7 data collection/analysis centers in the U.S. and Canada, 2 Cores (Data Management/Analysis and Pathology/Tissue Genotyping), and is guided by Steering and External Advisory ommittees. Our specific aims are: AIM 1. To validate linkage findings for gene discovery with a new, final sample of FPC families. We will (a) generate a validation sample of 85 new FPC pedigrees and follow up our ixisting cohort of FPC pedigrees to increase their informativeness; (b) perform a genomewide 5800 single nucleotide polymorphism (SNP) linkage analysis on this validation sample (genotyping will be sought at the Center for Inherited Disease Research at no cost to this grant); AIM 2. To perform a familial case-control association study to validate SNP associations identified in other consortia studies. We will genotype 500 FPC probands and 500 unrelated family controls using a custom SNP marker panel identified by the genomewide association studies of the Cohort Consortium, the Pancreatic Cancer Case-Control Consortium, and our own linkage analyses; and AIM 3. To identify the genes in candidate regions identified by linkage and association. We will (a) fine map regions identified through linkage analyses (including chromosomes 2p, 9p,17p, and 22q); (b) perform genomewide loss of heterozygosity allelotyping of microdissected early stage tumors (PanlNs and IPMNs) from FPC probands (comparing tumor to normal), with a focus on regions of interest; and (c) resequence the best candidate genes in the regions identified. Public Health Relevance: Over 32,000 new cases of pancreatic cancer occur in the U.S. each year, almost all rapidly fatal. Our research will help identify the genes for FPC, furthering knowledge about the etiology of pancreatic cancer that should accelerate translation to care. Risk assessment will be improved, and identified FPC genes will lead to development of more effective strategies for early detection, prevention, and therapy.